World Allergy Forum: The Epithelium as a Modulator of the Allergic Response

Introductions

Introduction
The Epithelium as a Modulator of the Allergic Response

Johannes Ring

Allergic diseases manifest in a variety of organs, most frequently, in the
skin and the mucous membranes, i.e. the border between the individuum and its
environment. Since the discovery of immunoglobin E, lymphocyte subpopulation
(TH1, TH2, TH 3?) the elucidation of the major histocompatibility complex (MHC)
and its role in antigen presentation together with the T-cell receptor the
pathophysiology of immediate-type allergic reactions has become clearer over the
last years.

At the same time, the autochthonous cells in the skin and in the airway
mucosa, especially the epithelial cells, have long been regarded only as
by-standers or inert structural components. However, it has been shown that
epithelial cells, such as kerationcytes in the skin – are able to produce
biologically active cytokines with possible relevance for the allergic
inflammation.

Until today, it is unknown why certain allergic reactions only take place in
the skin and not in the airway mucosa as well as why skin and respiratory atopic
diseases sometimes influence each other in a so called "alternate"
clinical course (changes from asthma to eczema and vice versa).

In this symposium the role of the epithelium – both in the respiratory
mucosa and in the skin – shall be discussed with regard to its effect in
modulating the deviated immune response in allergy. We hope to gain new
understanding for the pathophysiological mechanisms, particularly with regard to
environmental influences, as well as ideas for future strategies in therapy and
prevention

Introduction
The Epithelium as a Modulator of the Allergic Response

Stephen T. Holgate

Epithelial surfaces represent the interface between the
external and internal environments and therefore play a special role in
defending us against hostile factors. As a physical barrier, epithelia are
designed to repair rapidly once injured (healing by "primary"
intention) involving the elaboration of a range of growth factors such as the
epidermal-like growth factors, keratinocyte growth factor (FGF-7) and acidic
fibroblast growth factor (FGF-4). Upon epithelial injury the autocrine actions
of these factors drive epithelial migration and proliferative responses.

The epithelium is also host to importance immune cells that
sample the environment and, when appropriate, respond by driving defensive
immune and inflammatory responses. Notable amongst these are dendritic and
related Langerhans’ cells which are specialised to take up, process and
present allergens to T-cells involving MHC Class II and TCR respectively. For
effective immune responses co-stimulation is also required that engages adhesion
molecules such as CD80 (B-7.1) and CD86 (B-7.2) on APCs and CD28 on T-cells. The
direction which a T cell response is directed depends also on the cytokine
microenvironment IL-12/-18 selecting a Th-1 response and IL-10/PGE2
on Th-2 response. In allergic disease antigen processing is further enhanced by
Fce R1 and Fce
R2 which, through specific IgE, captures allergens and enhances their
uptake 100-1000-fold.

In asthma and eczematous there is increased loss of
epithelial cells following their premature apoptosis. In eczema this is probably
mediated by IFN-g secreted by activated T-cells
whereas, in asthma, it seems there is an intrinsic abnormality of epithelial
cells to enter programmed cell death especially when activated by enzymic
allergens or oxidant pollutants. The net result is epithelial loss and delayed
repair probably due to the enhanced secretion of members of the TGF-b
family of growth factors. These not only drive subepithelial fibroblasts to
generate excess repair collagens and matrix but also further inhibit epithelial
repair by competing with MAPK signalling. The consequence of these events is
impaired epithelial restitution and healing by "secondary intention"
(scarring).

The recognition that the epithelium is able to direct
organogenesis in the fetus involving the same pathways (apoptosis, EGF, TGF-b
) and activation of morphogenetic genes suggests that chronic inflammation and
tissue remodelling in chronic allergic disorders represents an extension of
morphogenesis. Understanding the intercellular and intracellular signalling
pathways involved in these processes will lead to new preventative and
therapeutic options which will increase tissue resistance to injury rather than
rely on suppressing inflammation. Understanding how the environment interfaces
with susceptibility genes in the epithelial-mesenchymal trophic unit will be the
challenge for the post-genome era.